Autosomal recessive Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a platelet storage pool defect, lysosomal accumulation of ceroid lipofuscin, pulmonary fibrosis, and death in the 5th decade. HPS occurs worldwide, but its incidence is highest in Puerto Ricans (PR). We studied 26 PR and 19 non-PR individuals, 3-35 years of age with HPS. A 16-bp duplication was found in 21 of 23 PR patients, and 0 of 17 non-PR patients in whom molecular analysis of the HPS gene was performed. A comparison of 16 PR adults (mean age 34y) with 7 non-PR adults (mean age 32y), demonstrated that the PR adults had lower forced vital capacities (82+/-25% vs 111+/-19%, p < 0.05). In addition, 9 of 16 adults with the 16-bp duplication, but 0 of 10 adults without the 16-bp duplication had DLCO values </- 80% of predicted (Fisher's 2-tailed, p=0.0039). Even if one non-duplication adult had a reduced DLCO, the odds ratio for risk of pulmonary fibrosis in 16-bp duplication-positive individuals is approximately 12.8 (95% confidence interval, 1.1-300). Ten 16-bp duplication-positive PR individuals with various degrees of pulmonary fibrosis were evaluated by bronchoalveolar lavage. There were 2-3 fold more cells in the BAL of 16-bp duplication-positive HPS than in that from normal individuals. The high resolution computerize axial tomography fibrosis score correlated with the %VC and FEV1 in this subset of HPS individuals (p=0.03 and 0.04, respectively). These studies document an increased risk of pulmonary fibrosis in Puerto Rican individuals with a 16-bp duplication in the Hermansky-Pudlak Syndrome gene. Further, they differentiate the 16-bp duplication-positive PR form of HPS from the non-PR form and provide the basis for a trial of anti-fibrotic agents in PR patients with HPS and significant restrictive disease.